We have developed the first user-friendly Negishi protocol capable of routinely cross-coupling all combinations of alkyl and aryl centers. The use of an easily synthesized, air stable, highly active, well-defined precatalyst PEPPSI-IPr (1; PEPPSI=pyridine-enhanced precatalyst preparation, stabilization and initiation; IPr=diisopropylphenylimidazolium derivative) substantially increases the scope, reliability, and ease-of-use of the Negishi reaction. All organohalides and routinely used pseudohalides were excellent coupling partners, with the use of chlorides, bromides, iodides, triflates, tosylates, and mesylates resulting in high yield of the coupled product. Furthermore, all reactions were performed by using general laboratory techniques, with no glove-box necessary as the precatalyst was weighed and stored in air. Utilization of this methodology allowed for the easy synthesis of an assortment of sterically encumbered biaryls and druglike heteroaromatics, demonstrating the value of the PEPPSI-IPr system. Furthermore, this is also the first time Pd-NHC (NHC=N-heterocyclic carbene) methodology has surpassed the related phosphine-ligated Negishi processes both in activity and use.

Pd-N-heterocyclic carbene (NHC)-catalyzed Buchwald-Hartwig amination protocols mediated by Pd-PEPPSI precatalysts is described. These protocols provide access to a range of hindered and functionalized drug-like aryl amines in high yield with both electron-deficient and electron-rich aryl- and heteroaryl chlorides and bromides. Variations in solvent polarity, base and temperature are tolerated, enhancing the scope and utility of this protocol. A mechanistic rationalization for base strength (pKb) requirements is also provided.

Cyclic allyl amines serve as useful tools in synthesis, [1] and are found in a vast number of naturally occurring alkaloids. [2] Preparation of cyclic allyl amines can be achieved by a number of classical methods such as the addition of allyl nucleophiles to cyclic imines and nitrones and subsequent reduction, [3] or Wittig reactions.[4] Such approaches, however, require harsh reaction conditions and have limited reaction scope. Milder methods include metal-catalyzed transformations such as intramolecular oxidative amination, [5] allylic amination, [6] and intramolecular hydroamination of allenes. [7] Ring-closing metathesis is perhaps the most convergent approach that renders itself well to rapid and modular assembly of a wide range of allyl amines. Herein, we show that allyl amines, which can be accessed using ring-closing metathesis and other straightforward methods, are convenient starting points for ring-contraction and ring-expansion reactions in which the conjugate acid of the nitrogencontaining nucleophile is enlisted as the leaving group. Our interest in the field of allyl amine chemistry stems from earlier studies of regioselectivity in palladium-catalyzed allylic amination. This work revealed the thermodynamic origin of linear selectivity in that reaction.[8] It later transpired that the isomerization had occurred as a result of having active Pd 0 species and acid in solution, and followed the mechanistic rationale shown in Scheme 1. Although this intermolecular process is largely undesirable and can be avoided, [9] it does suggest that an amine can play a dual role by first acting as the leaving group, and then as the nucleophile.[10]We envisioned straightforward access to complex allyl amines by skeletal isomerizations of readily accessible cyclic allyl amine scaffolds. This method can be strategically applied to late-stage modifications of complex amine-containing skeletons by using amine-containing fragments as both nucleophiles and as leaving group precursors.Amines that do not bear electron-withdrawing substituents have long been recognized for their reluctance to undergo palladium-catalyzed C À N bond scission.[10] In the course of our earlier studies of intermolecular allylic amination, we discovered that branched product selectivity is kinetic in origin when THF is used as the solvent, whereas linear products are formed as a result of acid-promoted branched-to-linear isomerization. High levels of branched selectivity were attained by introducing 1 equivalent of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) that prevented isomerization. We recently returned to this system and discovered that product isomerization was slow under these reaction conditions, and only 30 % of product isomerized after one week. Unexpectedly, in dichloromethane, branched allyl amines fully isomerized to form linear products within four days, even in the presence of DBU.[11] In addition, we have also observed the effect of solvent on kinetic branched/linear ratios in allylic amination. High branched regioselectivities we...

Transition-metal-catalyzed allylic amination has long been an area of intense research. 1 Allylamines have previously been prepared using iridium 2 and rhodium 3 catalysts with high selectivities for the branched products. On the other hand, the use of palladium in this chemistry has been known to produce linear allylamines with few notable exceptions. 4 This phenomenon has been obscure for some time. The goal of this contribution is to shed light on this long-standing problem and to evaluate ways of exercising control over selectivity with palladium catalysts.We recently demonstrated an instructive aberration in palladiumcatalyzed allylic amination: unsubstituted aziridines were found to give preferential formation of branched allylated products. 5 Mechanistic investigations indicate that amines other than aziridines undergo branched/linear (b/l) isomerization to form the thermodynamically more stable linear products. 5,6 It was found that protic acid generated during the reaction is the prerequisite for product isomerization. 5 Palladium coordination to the double bond of the protonated allylamine initiates ionization of the kinetically favored branched product (Figure 1). We consequently sought conditions under which the proton can be scavenged without detrimental effect on catalytic turnover such that the linear product formation can be suppressed.

The enantioselective synthesis of maoecrystal V, a cytotoxic polycyclic diterpene, is described. Key reactions in the synthesis include an intramolecular Heck reaction, an oxidative cycloetherification, and an intermolecular Diels-Alder reaction to forge the carbocyclic core in a concise and stereoselective manner. Late-stage amine and C-H oxidation is used to install the final functional groups required to complete the synthesis.